Tramadol produces analgesia by a dual mechanism. Identify both components and the CYP enzyme relevant to its activation:
- A Weak mu-opioid agonism plus GABA-A potentiation; activated by CYP3A4
- B Weak mu-opioid agonism plus norepinephrine and serotonin reuptake inhibition; parent drug is the monoaminergic component and O-desmethyltramadol (CYP2D6 product) is the opioid component ✓
- C Kappa and delta opioid agonism plus acetylcholine release; activated by CYP2C19
- D Sigma receptor agonism plus serotonin reuptake inhibition; CYP3A4-independent
Correct answer: B. Weak mu-opioid agonism plus norepinephrine and serotonin reuptake inhibition; parent drug is the monoaminergic component and O-desmethyltramadol (CYP2D6 product) is the opioid component
Explanation
Tramadol itself (and its M1 metabolite O-desmethyltramadol) act at mu-opioid receptors while the parent drug also inhibits neuronal reuptake of norepinephrine and serotonin (similar to SNRIs), contributing to descending pain inhibition. O-desmethyltramadol (M1), formed by CYP2D6, has 200-fold higher mu receptor affinity than tramadol and accounts for most opioid analgesia. CYP2D6 poor metabolizers have reduced analgesia; ultra-rapid metabolizers are at risk for opioid toxicity.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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